UPLC-MS/MS法测定坎地沙坦酯原料药及片剂中3种遗传毒性杂质的含量  

Determination of Three Genotoxic Impurities in Candesartan Cilexetil Raw Materials and Tablets by UPLC-MS/MS Method

作　　者：吴月霞 杨秋红 陈杰 WU Yue-xia;YANG Qiu-hong;CHEN Jie(Henan Institute for Drug and Medical Device Inspection(Henan Vaccine Issuance Center),Henan Zhengzhou 450018,China)

机构地区：[1]河南省药品医疗器械检验院(河南省疫苗批签中心),河南郑州450018

出　　处：《中国药物评价》2024年第5期362-367,共6页Chinese Journal of Drug Evaluation

基　　金：河南省市场监督管理局科技计划(HNSCJGK202417)。

摘　　要：目的:建立超高效液相色谱串联三重四极杆质谱法(UPLC-MS/MS法)快速测定坎地沙坦酯原料药及片剂中2-[(叔丁氧基羰基)氨基)]-3-硝基苯甲酸乙酯、2-氰基-4′-溴甲基联苯和2-[(2-氰基联苯-4-基)甲基]氨基-3-硝基苯甲酸乙酯3种遗传毒性杂质的含量。方法:采用Waters Cortecs@T3色谱柱(2.1 mm×100 mm,2.7μm),以乙腈-0.1%甲酸水溶液(55∶45)为流动相,等度洗脱,流速为0.5 mL·min^(-1),柱温30℃;进样体积5μL。质谱采用电喷雾(ESI)离子源,多反应监测(MRM)正离子检测模式进行定量分析。结果:3种目标杂质均在0.1~2.0μg·mL^(-1)浓度范围内(相当于主成分的0.002%~0.04%水平;3种目标杂质限度为0.02%,总量限度为0.06%)与峰面积线性关系良好(r≥0.9991);平均加标回收率为98.6~107.5%,RSD为0.3~2.2%。检测限分别为0.0004~0.15 ng·mL^(-1),定量限分别为0.001~0.51 ng·mL^(-1),基本满足目标杂质的检测灵敏度要求。经检验,6批次样品中,3种杂质含量均不超过定量限浓度,均符合规定。结论:本方法操作简单、灵敏准确,在规定限度范围内呈线性响应,分析时间短至8 min,可为研究其他药物中此类杂质提供参考。Objective:To establish an UPLC-MS/MS method for the rapid determination of three genotoxic impurities,2-((tert-butoxy-carbonyl)amino-3-nitrobenzoate,2-cyano4′-bromo-methyl biphenyl and 2-[[(2-cyanobiphenyl-4-yl)methyl]amino]-3-nitrobenzoate in candesartan cilexetilraw materialsand tablets.Methods:The chromatography was performed on Waters Cortecs T3 column(2.1 mm×100 mm,2.7μm).Acetonitrile-0.1%formic acid aqueous solution(55∶45)was used as the mobile phase at a flow rate of 0.5 mL·min^(-1).The column temperature was 30℃,Sample size 5μL.The mass spectrometry was quantitatively analyzed by electrospray(ESI)ion source and multiple reaction monitoring(MRM)positive ion detection mode.Results:The 3 kinds of target impurities were all in the concentration range of 0.1-2.0μg·mL^(-1)(equivalent to 0.002%-0.04%of the principal component.The 3 target impurity limit was 0.02%,the total limit was 0.06%)and the peak area had a good linear relationship(r≥0.9991).The average recoveries were 98.6-107.5%and RSD were 0.3-2.2%.The detection limits were 0.0004-0.15 ng·mL^(-1),and the limits of quantification were 0.001-0.51 ng·mL^(-1),respectively,which basically met the detection sensitivity requirements of target impurities.After inspection,the contents of 3 kinds of impurities in 6 batches of samples did not exceed the limit of quantitative concentration,and all met the regulations.Conclusion:The method is simple,sensitive and accurate,with a linear response within the specified limit,and the analysis time is as short as 8 min,which can provide a reference for the study of such impurities in other drugs.

关 键 词：遗传毒性杂质 超高效液相色谱串联三重四极杆质谱法 坎地沙坦酯 含量测定 2-(叔丁氧基羰基)氨基-3-硝基苯甲酸乙酯 2-氰基-4′-溴甲基联苯 2-[(2-氰基联苯-4-基)甲基]氨基-3-硝基苯甲酸乙酯 

分 类 号：R927.1[医药卫生—药学] R972.4